The global HIV epidemic is spreading rapidly in women, and additional research is warranted to examine important immune differences that may uniquely alter the course of HIV disease between women and men. The female sex hormone, estrogen, is a potent enhancer of cell-mediated immunity that drives more effective immune responses to pathogens and vaccination in women (compared to men). The overall objective of this research proposal is to examine the influence of female sex hormones on HIV immunopathogenesis in women. This research proposal will test the hypothesis that menopause, marked by a precipitous decline in estrogen, will lead to changes in immune function that may compromise immunologic control of HIV. A retrospective longitudinal analysis will be used to examine effects of menopause in 100 HIV-infected women and 50 HIV- uninfected women. The specific aims of this work are 1) Investigate the effects of menopause on T-cell function in HIV infected women, including antigen specific responses and cellular proliferation. We will also quantify functionally important T-cell subpopulations including T-cell maturation stages, T-cell activation, and regulatory T cells, and 2) Distinguish the impact of HIV disease status on immune changes associated with menopause by comparing identical immune analyses in 50 HIV-uninfected women to distinguish global immune effects of menopause and advancing age from those that characterize HIV disease. We will also compare immune effects of menopause in women with different clinical states of HIV disease, such as untreated long term non-progressors and treated antiretroviral responders. If successful, this work could provide a rationale for further exploration of sex hormone influences on HIV immunopathogenesis or the design of appropriate interventions targeted at disease pathophysiology. It is expected that 50% of HIV-infected patients in the U.S. will be 50 years or older by 2015, thus these findings could be relevant to the care of aging HIV-infected women. PUBLIC HEALTH RELEVANCE: The global HIV epidemic is spreading rapidly in women, and additional research is needed to examine important immune differences that may uniquely alter the course of HIV disease in women. The female hormone, estrogen, is an enhancer of immune function that drives strong immune responses against viruses. The purpose of this study is to examine whether loss of estrogen with menopause makes it more difficult for the HIV-infected women to mount an immune attack against HIV.